17alpha-bromo-6alpha-fluoroprogesterone



United States Patent NoDrawing. Applica i October, 1958 1 ciaim. to,260-3913 This invention relates to steroid compounds and is moreparticularly concerned with '17a-'bromo-6a-fiuorotional agents.

subcutaneously.

2,924,610 j Patented Feb. 9, 1960 tion at carbon atom No. 6 is invertedby treatment with "a strong mineral acid such as hydrochloric acid toyield 17a-bromo-6a-fluoro-4-pregnen-3,20 dione 6a-fluoropr'ogester'one)(VI).

I The, compounds of this invention are useful as progesta-17a-bromo-6a-fiuoroprogesterone is proorally "or nu-broa gestationallyactive when administered either The following examples, which are to beconstrued as illustrat ve ratherthan limiting, give details of theproductsand processes of the present invention.

' EXAMPLE 1 1 7 z-bromopr egnenolone acetate (I) 4epregnen3,20-dione1-7u-bromo-6a fluoroprogesterone) intermediates in, the productionthereof, and a process for their preparation. 7

The new compounds and the process of the present invention may beillustratively represented as follows:

CII:

A mixture of 5.0 grams of 17oi-bromopregnenolone, ml, of aceticanhydride, and 0.2 gram of p-toluenesulfonic acid was warmed until "thesteroid had allv dissolved. On cooling, l7a-bromo-pregnenolone acetateprecipitated, which, after filtering, washing with water and drying,melted at 148-150 C.

I II

(EH: CH: CH: 0:0 (5 0 =0 o=c o I no 1 Hi) 110 l F F VI V IV wherein R isan acyl radical of hydrocarbon carboxylic acid containing from 1 to 12carbon atoms inclusive.

The process of the present invention starts with 3 acylates of the knowncompound l7u-bromopregnenolone. 17a-bromopregnenolone is described in apublication by Engel and Jahnke, Can. J. Biochem. PhysioL, 35, 1047(1957).

The 3-acylates of the known l7a-bromopregnenolone (I) are treated with aperacid such as peracetic, perbenzoic, and monoperphthalic to obtain17a-bromo-3B- acyloxy-Sm,6a-epoxypregnan-20-one (II). The epoxide II isallowed to react with a fluorinating agent such as hydrogen fluoride orboron trifluoride to givel7a-bromo-3fiacyloxy-6fi-fluoro-5a-hydrQXypregnan-ZO-one (III). Thefluorohydrin III is hydrolyzed under acid conditions, for example withperchloric acid in methanol, to yield 170:-b-romo-6fi-fluoro-3B,5adihydroxypregnan 20 one (IV). The dihydroxycompound IV is treated with an oxidizing agent, such as sodiumdichromate in acetic acid, to give The hydroxy-diketone V is dehydrate;and the configure;

Similarly, other esters of 17a-bromopregnenolone may be prepared bytreating 17u-bromopregnenolone, in the presence of an acidic or basiccatalyst, with the anhydrides or acyl halides of organic carboxylicacids, particularly hydrocarbon carboxylic acids, containing from one totwelve carbon atoms, inclusive.

EXAMPLE 2 1 7a-br0m0-3,8-acet0xy-5ot,6a-ep0xypregnan-20-0ne (ll To asolution of 2.00 grams of l7a-bromopregnenolone acetate in 60 ml. ofchloroform cooled to 10 C. was added a solution of 0.93 gram ofmonoperphthalic acid in 27.5 ml. of ether. The mixture was left at roomtemperature for 42 hours, filtered from insoluble material, washed with10 percent sodium bicarbonate solution and water, dried, and evaporated.The solid residue was recrystallized from ethyl acetate, yielding17a-bromo-3 8- acetoxy-S11,6a-epoxypregnamZO-one, melting at 187- 189.5C.

...EXAMPLE 3 By crystallization from a mixture of methylene chloride andmethanol, 2. sampleof l7a-brorrio-3fl-acetoxy- 6gfluoro-a-hydrXypregnan-ZO-One was ra btainecl with a' melting point of 170 C. (dec.).

EXAMPLE4 A mixture of 0.20 gram of 17a-bromo-3B-acetoxy-6B-fluoro-Sa-hydroxypregnan-20-one, 4 ml. 'of methanol, and 0.15 ml. of 70percent perchloric acidwas-heated until the solid had dissolved and thenleft atroom temperature for 17 hours. The crystalline solidwhichprecipitated on dilution with water was recrystallized frommethanol-water, yielding17a-b1'OIIiO-6fi-flll0lO-3fi,5a-dihydroxypregnan-ZO-one with a meltingpoint of 168 C. (dec.). y 7

EXAMPLE 5 17a-bromo-6fi-fluor0-5a-hydroxypregnan-3,20-dione (V) ofsodium dichromate dihydrate in 50 ml. of aceticacid,"

and the resulting mixture was allowed to stand at room temperature for17 hours. Five ml. of methanol was then, added, followed by 125 ml. ofwatery ,Thepreci itated solid was filtered, dried and recrystallizedfrom isopropanol, yielding17a-bromo-6fl-fluoro-5a-hydroxypregnan-3,20-dione melting at 176 C.(dec.).

EXAMPLE 6 17a-bromo-6wflrioroprogesterone (VI) A suspension of 1.6 gramsof 17a-bromo-6fi-fluoro-5uhydroxypregnan-3,20-dione in ml. of aceticacid was cooled to about -15 C. and anhydrous hydrogen chloride waspassed through the mixture for one hour. The solid dissolved to give ayellow solution, during thefirst 15 minutes. After standing for-anadditional hour, the solution was cooled in ice and ml. of water wasadded slowly which precipitated 1.3 grams-of a yellowish solid. Thisproduct was dissolved in benzene and chromatographed on 40 grams ofneutral alumina. Elution with 500 m1. of-benzene yielded 1.2 grams ofcolorless solid which was crystallized from a mixture of acetone andhexane. .The l7a-bromo-6a-fiuoroprogesterone thus obtained melted at1735-1765 C. (dec.). It had an ultraviolet absorption maximum at 237millimicronsyand' infrared maxima, in carbon disulfide solution, at 1710and I claim: 17a-bromo-6a-fluoro-4-pregnem3,ZO-dione.

References Cited in the file of this patent UNITED STATES PATENTS Fieserand Fieser: Natural Products Related to Phenanthrene, page 228.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION February 9 1960Patent No. 2,924, 610

David J. Marshall It is hereby certified that error appears in theprinted specification of the above numbered patent requiring correctionand that the said Letters Patent should read as corrected below.

Column '1, line 52, for "of hydrocarbon" read of a line 72, for"dehydrate"- read dehydrated;; d heading to EXAMPLE 4 hydrocarbon column3 lines 17 and l8 the italicize w instead of as in the patent:

Should appear as shown helo 17 -bromo6 B-fluor03[3',5 dihydroxypregnan-20-one (IV) Signed and sealed this 11th day of October 1960.

(SEAL) Attest:

KARL H. AXLINE ROBERT C. WATSON Commissioner of Patents AttestingOfficer

